Characteristics of primary sclerosing cholangitis in the USA

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology that is frequently associated with inflammatory bowel disease. It is characterized by diffuse inflammation and fibrosis of the biliary tree, and it usually leads to biliary cirrhosis and portal hypertension. PSC is most commonly diagnosed with endoscopic retrograde cholangiopancreatography, although magnetic resonance cholangiography (MRC) is rapidly emerging as a first choicediagnostic test. MRC has the advantage of being non-invasive, does not require radiation, and is cost-effective in that it does not carry the risk of pancreatitis associated with retrograde studies. ² Percutaneous cholangiography is seldom performed anymore.     

A Prospective Randomized Trial of Steroid-Free Maintenance Regimens in Kidney Transplant Recipients—An Interim Analysis

We compared three maintenance immunosuppressive regimens in a rapid discontinuation of prednisone protocol. From March 1, 2001, through December 31, 2003, 239 first and second kidney transplant recipients (166 LD; 73 DD) were randomized. All recipients were treated with Thymoglobulin; all received steroids intraoperatively and for 5 days postoperatively. Randomization was to cyclosporine-mycophenolate mofetil (n = 85); high-level tacrolimus (TAC) (8-12 ng/mL)-low-level sirolimus (SRL) (3-7 ng/mL) (n = 72); or low-level TAC (3-7 ng/mL)-high-level SRL (8-12 ng/mL) (n = 82). We found no difference at 24 months between groups in patient, graft, death-censored graft, or acute rejection-free graft survival, or in kidney function. Wound complications were more common in SRL-treated recipients (p = 0.02); we found no other differences between groups in complication rates. Our data suggest that excellent patient and graft survival and low rejection rates can be obtained using a variety of maintenance protocols without prednisone.     

Chronic exposure of rats to cognition enhancing drugs produces a neuroplastic response identical to that obtained by complex environment rearing.

Recent data suggest that Alzheimer's patients who discontinue treatment with cholinesterase inhibitors have a significantly delayed cognitive decline as compared to patients receiving placebo. Such observations suggest cholinesterase inhibitors to provide a disease-modifying effect as well as symptomatic relief and, moreover, that this benefit remains after drug withdrawal. Consistent with this suggestion, we now demonstrate that chronic administration of tacrine, nefiracetam, and deprenyl, drugs that augment cholinergic function, increases the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing. While both drug-treated and complex environment reared animals continue to exhibit memory-associated activation of hippocampal polysialylated neurons, the magnitude is significantly reduced suggesting that such interventions induce a more robust memory pathway that can acquire and consolidate new information more efficiently. This hypothesis is supported by our findings of improved learning behavior and enhanced resistance to cholinergic deficits seen following either intervention. Furthermore, the level of enhancement of basal neuroplastic status achieved by either drug or environmental intervention correlates directly with improved spatial learning ability. As a combination of both interventions failed to further increase basal polysialylated cell frequency, complex environment rearing and chronic drug regimens most likely enhanced cognitive performance by the same mechanism(s). These findings suggest that improved memory-associated synaptic plasticity may be the fundamental mechanism underlying the disease modifying action of drugs such as cholinesterase inhibitors. Moreover, the molecular and cellular events underpinning neuroplastic responses are identified as novel targets in the search for interventive drug strategies for the treatment of neurodegenerative and neuropsychiatric disorders.     

Reactivation of dormant lumbar methicillin-resistant Staphylococcus aureus osteomyelitis after 12 years.

The adequate treatment of methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis has intrigued clinicians for some time. As the resistance of these pathogens, coupled with the increase in community-acquired cases, continues steadily to rise, clinicians are finding it useful to employ multi-modal approaches for efficacious treatment. The authors present a single case report of a patient with recurrent MRSA osteomyelitis, lumbar paraspinal and epidural abscess. He was found to have decreased muscle strength and was hyporeflexic in the involved extremity. Serum testing demonstrated MRSA bacteremia. Neuroimaging studies revealed evidence of paraspinal abscess and a presumed herniated nucleus pulposus at the L5/S1 interspace with significant nerve root compromise. Despite antimicrobials, his symptoms persisted, necessitating surgical exploration. At surgery, paraspinal and epidural abscesses were encountered and debrided; however, no herniated disc was visualized. This case demonstrates the diagnostic and therapeutic dilemmas with which these lesions present. We postulate that the MRSA osteomyelitis/discitis pathogens were walled off in the disc space and subsequently inoculated the soft tissues with ensuing bacteremia. We concur that antimicrobial treatment should be the first line of therapy for these patients; however, surgical debridements and cautious spinal instrumentation should be employed where appropriate.     

Primary malignant melanoma: a rare cause of mediastinal mass

A case of primary malignant melanoma in the mediastinum presenting as recurrent laryngeal nerve palsy is reported. Tissue biopsy at mediastinotomy yielded a diagnosis of malignant melanoma. The mass was fixed to the left aspect of the trachea and to the upper border of the left main bronchus and could not be removed surgically. Further extensive clinical and radiological investigations revealed no evidence of tumor elsewhere in the body.     

Voltage Oscillations in Xenopus Spinal Cord Neurons: Developmental Onset and Dependence on Co-activation of NMDA and 5HT Receptors

The development of intrinsic, N-methyl-D-aspartate (NMDA) receptor-mediated voltage oscillations and their dependence on co-activation of 5-hydroxytryptamine (5HT) receptors was explored in motor neurons of late embryonic and early larval Xenopus laevis. Under tetrodotoxin, 100 μM NMDA elicited a membrane depolarization of around 20 mV, but did not lead to voltage oscillations. However, following the addition of 2–5 μM 5HT, oscillations were observed in 12% of embryonic and 70% of larval motor neurons. The voltage oscillations depended upon co-activation of NMDA and 5HT receptors since they were curtailed by selectively blocking NMDA receptors with D-2-amino-5-phosphonovaleric acid (APV) or by excluding Mg²⁺ from the experimental saline. 5HT applied in the absence of NMDA also failed to elicit oscillations. Oscillations could be induced by the non-selective 5HT_1a receptor agonist, 5-carboxamidotryptamine (5CT) and both 5HT- and 5CT-induced oscillations were abolished by pindobind-5HT₁, a selective 5HT_1a receptor antagonist. To test whether 5HT enables voltage oscillations by modulating the voltage-dependent block of NMDA channels by Mg²⁺, membrane conductance was monitored under tetrodotoxin. Although 5HT caused membrane hyperpolarization of 4–8 mV, there was little detectable change in conductance. NMDA application caused an approximate 20 mV depolarization and an ‘apparent’ decrease in conductance, presumably due to the conductance pulse bringing the membrane into a voltage region where Mg²⁺ blocks the NMDA ionophore. 5HT further decreased conductance, which we propose is due to its enhancement of the voltage-dependent Mg²⁺ block. When the membrane potential was depolarized by ～20 mV via depolarizing current injection (to mimic the NMDA-induced depolarization), 5HT increased rather than decreased membrane conductance. Furthermore, 5HT did not affect the increase in membrane conductance following NMDA applications in zero Mg²⁺ saline. The results suggest that intrinsic, NMDA receptor-mediated voltage oscillations develop in a brief period after hatching, and that they depend upon the co-activation of 5HT and NMDA receptors. The enabling function of 5HT may involve the facilitation of the voltage-dependent block of the NMDA ionophore by Mg²⁺ through activation of receptors with 5HT_1a-like pharmacology.     

Blood flow acceleration in the carotid and brachial arteries of healthy volunteers: respective contributions of cardiac performance and local resistance

Summary— The influence of local resistance and cardiac performance on peripheral blood acceleration was investigated in 14 healthy male volunteers. Steady and pulsatile flow was studied in the brachial and in the common carotid arteries, ie, two territories that exhibit marked differences in resistive characteristics. Instantaneous blood velocity (V), mean blood velocity (V_m) and artery diameter (D) were evaluated at rest by an ultrasonic range-gated pulsed Doppler flowmeter using a double transducer probe, thus allowing the calculation of mean blood flow (Q). Mean local resistance (R) was obtained by dividing the mean arterial pressure by Q. The peak value of the local acceleration of the blood was obtained by computer-assisted calculation of the first derivative of instantaneous blood velocity (G_max = +dV/dt_max). Peak aortic blood acceleration (GAo) was simultaneously measured from the suprasternal notch using a pulsed Doppler velocity meter. In the brachial and the common carotid arteries, G_max was of a similar magnitude (551 ±30 and 555 ± 44 cm/s², respectively) despite major differences in the respective D, V_m, Q and R values. In neither artery was there a relationship between G_max and either resting Q or R. At the brachial artery level, G_max was positively related to GAo ( r = 0.79, P = 0.0008). At the common carotid artery level, there was a weak, although non significant relationship between G_max and GAo ( P = 0.08). Our results indicate that the local acceleration of peripheral blood flow in the brachial artery is related rather to upstream central impulse than to downstream hemodynamics, and suggest some regional differences in the hemodynamic determinants of the local acceleration of peripheral blood flow.     

Diagnostic accuracy of progressive supranuclear palsy in the Society for Progressive Supranuclear Palsy brain bank.

Diagnostic accuracy has been addressed previously for Parkinson's disease in a brain bank collection, but accuracy of progressive supranuclear palsy (PSP) has not been addressed in a similar setting. Clinical and genetic features of pathologically confirmed cases of PSP were compared with misdiagnosed cases to determine ways to improve diagnostic accuracy. Medical records were reviewed for 180 cases sent to the Society of Progressive Supranuclear Palsy Brain Bank that had standardized neuropathologic evaluations as well as determination of apolipoprotein E and tau genotypes. Of the 180 cases studied, 137 had PSP and 43 had other pathologic diagnoses. Corticobasal degeneration (CBD), multiple system atrophy (MSA), and diffuse Lewy body disease (DLBD) accounted for 70% of the misdiagnosed cases. History of tremor, psychosis, dementia, and asymmetric findings were more frequent in misdiagnosed cases. The frequency of H1 tau haplotype (93 vs. 80%) and H1H1 genotype (86 vs. 66%) were significantly greater and APOE epsilon4 carrier state was significantly less (17 vs. 41 %) in PSP compared with misdiagnosed cases. Pathologic evaluation of clinically diagnosed PSP remains important for definitive diagnosis, and CBD, MSA, and DLBD are the disorders most likely to be misdiagnosed as PSP. Tremor, psychosis, early dementia, asymmetric findings, absence of H1 haplotype, and presence of APOE epsilon4 should raise questions about a diagnosis of PSP.