HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy

Introduction of highly active antiretroviral therapy (HAART) has been associated with many changes in the complications of human immunodeficiency virus (HIV) infection. A cohort of 25 HIV patients with progressive multifocal leukoencephalopathy (PML) treated with HAART experienced a median survival of >46 weeks. This is an improvement in prognosis compared with recent historic experience and correlated with HIV RNA viral load reductions. We conclude that current HIV therapy is important in improving the outlook of PML in the setting of HIV.     

The representation of pleasant touch in the brain and its relationship with taste and olfactory areas

Although there has been much investigation of brain pathways involved in pain, little is known about the brain mechanisms involved in processing somatosensory stimuli which feel pleasant. Employing fMRI it was shown that pleasant touch to the hand with velvet produced stronger activation of the orbitofrontal cortex than affectively neutral touch of the hand with wood. In contrast, the affectively neutral but more intense touch produced more activation of the primary somatosensory cortex than the pleasant stimulus. This indicates that part of the orbitofrontal cortex is concerned with representing the positively affective aspects of somatosensory stimuli, and in further experiments it was shown that this orbitofrontal area is different from that activated by taste and smell. The finding that three different primary or unlearned types of reinforcer (touch, taste, and smell) are represented in the orbitofrontal cortex helps to provide a firm foundation for understanding the neural basis of emotions, which can be understood in terms of states elicited by stimuli which are rewarding or punishing.     

A study of oligoclonal band negative multiple sclerosis.

OBJECTIVES--To determine whether oligoclonal band (OCB) negative multiple sclerosis is a reliable diagnosis and, if so, whether it has a distinctive prognosis. METHODS--Retrospective and matched prospective comparison of the clinical and laboratory features of patients with clinical definite multiple sclerosis with and without intrathecal synthesis of oligoclonal IgG. RESULTS--Thirty four patients were identified with apparent OCB negative clinically definite multiple sclerosis. The results of oligoclonal banding proved to have been equivocal in 14 of 34; the clinical diagnosis of multiple sclerosis was questionable in 8 of 34. The remaining 12 patients with "true" OCB negative multiple sclerosis were significantly less disabled than matched OCB positive controls. Re-examination of CSF-serum pairs from six OCB negative patients showed that three remained OCB negative while three showed evidence of intrathecal synthesis of OCBs. CONCLUSIONS--OCB negative clinically definite multiple sclerosis is rare and should be diagnosed with caution; in unequivocal cases it seems to have a relatively benign prognosis.     

Laser Induced Autofluorescence Diagnosis of Bladder Cancer

Purpose

We assessed the ability of laser induced autofluorescence to differentiate malignant from nonmalignant bladder lesions.

Materials and Methods

We studied 53 patients with bladder cancer undergoing mucosal biopsies or transurethral resection of a bladder tumor. A quartz optical fiber was advanced through the working channel of a cystoscope and placed in gentle contact with the bladder. Tissue fluorescence was excited by 337 nm. light pulses (nitrogen laser). One fiber was used for transmission of the excitation and emission (fluorescence) light. An optical multichannel analyzer system was used to record fluorescence spectra of the sites of interest.

Results

We analyzed the fluorescence spectra of 114 bladder areas (1 carcinoma in situ as well as 28 malignant, 35 inflammatory, 7 dysplastic, 1 squamous metaplastic and 42 normal areas). These lesions included 44 difficult to diagnose suspicious tumors (11 malignant and 33 nonmalignant). We developed an algorithm that used the I385:I455 nm. fluorescence ratio to distinguish malignant from nonmalignant lesions, including inflammatory areas. By analyzing the data on all 114 lesions, we noted the sensitivity, specificity, and positive and negative predictive values of this method for differentiating malignant from nonmalignant bladder lesions to be 97, 98, 93 and 99 percent, respectively.

Conclusions

Under excitation with 337 nm. light a clear differentiation between malignant and nonmalignant bladder tissues can be made using the I385:I455 nm. autofluorescence ratio.     

Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR

Cystic fibrosis (CF) is caused by mutations in the gene encodinga chloride channel called the CF transmembrane conductance regulator(CFTR). A single mutation in this gene, deletion of three nucleotidesthat leads to the absence of phenylalanine 508 (i.e., F508),is found on 70% of all CF chromosomes. To explore the molecularmechanism(s) responsible for defective chloride transport inpatients with CF, we have studied the processing, localization,and function of wild type (W.T.), F508 and G551D CFTR (a GDmissense mutation at position 551) in retrovirus transducedL cells. Cell transduced with W.T. CFTR expressed a 170 kd CFTRprotein that was endoglycosidase H (Endo H) resistant, localizedto the plasma membrane, and generated a cAMP-mediated anionconductance (G_Cl) when stimulated with standard concentrationsof forskolin (5 µM), cpt cAMP (400 µM) and IBMX(100 µM). The G551D CFTR was indistinguishable from W.T.CFTR with respect to post-translational processing and localization,but it did not produce a cAMP-activated G_CI in response to thestandard stimulation cocktail. However, raising the IBMX concentrationto 4 mM produced Gc, in G551D expressing cells. Cells transducedwith F508 CFTR expressed an Endo H sensitive CFTR protein (140kd) that was found in a cytosolic, perinuclear location. Thesecells did not respond to the standard cocktail, but 20% of cellsincreased G_CI when the cocktail contained 4 mM IBMX. Incubationof cells at 26°C for 48 hours prior to analysis elicitedresponses in F508 expressing cells at low IBMX concentrations,but had no effect on the responses of cells expressing W.T.or G551D CFTR. The response of F508 to 26°C was associatedwith plasma membrane localization of CFTR protein. These resultssuggest that there are two mechanisms whereby CFTR mutationslead to loss of cAMP-responsive GCI. First, shown by G551D CFTR,the protein can be processed and targeted to the plasma membranecorrectly, but lack full responsiveness to stimulation by cAMP.Second, as examplified by F508 CFTR, a partially functionalprotein which is not targeted to its correct cellular locationcan also lead to loss of the cAMP, responsive G_CI.     

Diffusion of information about genetic risk within families

Recent developments in genetics are likely to exacerbate the ethical issues in clinical practice, especially with regard to privacy and disclosure of genetic information. To evaluate the behaviour of patients with respect to transmitting carrier information, we undertook a survey of 283 families with a balanced chromosomal rearrangement as a model. In these families, 1816 relatives were considered at risk and 806 of them were karyotyped (44.4%). The percentage of karyotypes performed is significantly related to the number of living children of the index couple, the reason for referral, the nature of the anomaly, the training of the counsellor and the age of the index case. This study shows the limits of the screening of at risk individuals within families, based on the willingness of the patients, and addresses practical and ethical issues around family disclosure in medical genetics.     

Pharmacokinetics of methotrexate in leukemia cells: Effect of dose and mode of injection

A lumped compartmental model has been derived to predict methotrexate concentration as a function of time for L1210 cells in BD2F ₁ female mice at doses ranging from 3 mg/kg to 400 mg/kg. Using standard methods of parameter estimation as well as experimental determinations, an integrated approach was derived to account for the differences between the subcutaneous (s.c.) and intraperitoneal (i.p.) modes of injection. It was found that a single generalized forcing function can be used to fit plasma concentration after s.c. injection for all doses. Adequate fits (average error<20% while the standard deviation of experimental determinations was±22%) of L1210 cell data after s.c. injection were obtained. The best results were for a maximum facilitated influx constant V_max of 0.424 g/min/ml, a Michaelis influx constant K_m of 1,42 g/ml, and a first-order efflux constant of 0.047 min^–1.The model simulations were not sensitive to V_max, K_m,and so long as the ratio V_max/was approximately 9g/ml. The values of V _max ,K _m ,and which were obtained from our analysis of the in vivodata can be explained on the basis of previously performed in vitroexperiments. The parameters obtained from modeling the s.c. data were then applied for i.p. injection data. The resulting fits were adequate (average error<20% while the standard deviation of experimental determinations was±22%). A single generalized forcing function for drug concentration in the peritoneal cavity after i.p. injection for all doses was derived. The application of these results enables the prediction of methotrexate concentration in neoplastic cells at other doses after either s.c. or i.p. injection.     

Delayed muscle soreness: a review

There are two generally recognized types of muscular pain or soreness associated with severe exercise. These two types are a) acute soreness and b) delayed soreness. Acute soreness or pain occurs during and immediately following exercise. This condition is short-lived and is alleviated when exercise is discontinued. Acute soreness is thought to be associated with lack of adequate blood flow or ischemia to the active muscles. The more serious problem associated with severe exercise is delayed muscle soreness, i.e., pain and soreness that occurs 24 to 48 hours after exercise. Four popular theories of the etiology of this condition are: lactic acid accumulation, spasms, torn tissue, and connective tissue damage. These theories are discussed in light of current biochemical and morphological findings. From recent studies designed to induce delayed soreness, it has been found that the degree of delayed soreness experienced with exercise is related to the type of muscle contraction performed. Maximum soreness is associated with eccentric types of contractions. A possible explanation for this finding is presented.J Orthop Sports Phys Ther 1983;5(1):10-13.     

The role of endorphins in exercise: a review of current knowledge

Exercise training is used increasingly to prevent and treat disease, and millions of healthy persons participate in various aerobic-type sports; yet, the mechanisms by which exercise produces various clinical effects is imperfectly understood. Emerging evidence suggests that the endogeneous opioid endorphins may be involved in two widely varying aspects of exercise: endocrine control and behavior and mood adaptation. The present paper summarizes these findings. The relationship of endorphins and adrenocorticotropin to stress and the aspects of endorphins' involvement in the concept of "runner's high" are discussed. J Orthop Sports Phys Ther 1983;4(3):169-173.