Ketogenic diet as a potential intervention for lipedema.

Lipedema (LI) is a common yet misdiagnosed condition, often misconstrued with obesity. LI affects women almost exclusively, and its painful and life-changing symptoms have long been thought to be resistant to the lifestyle interventions such as diet and exercise. In this paper, we discuss possible mechanisms by which patients adopting a ketogenic diet (KD) can alleviate many of the unwanted clinical features of LI. This paper is also an effort to provide evidence for the hypothesis of the potency of this dietary intervention for addressing the symptoms of LI. Specifically, we examine the scientific evidence of effectiveness of adopting a KD by patients to alleviate clinical features associated with LI, including excessive and disproportionate lower body adipose tissue (AT) deposition, pain, and reduction in quality of life (QoL). We also explore several clinical features of LI currently under debate, including the potential existence and nature of edema, metabolic and hormonal dysfunction, inflammation, and fibrosis. The effectiveness of a KD on addressing clinical features of LI has been demonstrated in human studies, and shows promise as an intervention for LI. We hope this paper leads to an improved understanding of optimal nutritional management for patients with LI and stimulates future research in this area of study.

Proteinuria is a risk factor for mortality over 10 years of follow-up. MRFIT Research Group. Multiple Risk Factor Intervention Trial.

Proteinuria has been shown to be strongly associated with the prevalence and incidence of cardiovascular disease. It has been difficult to determine if the link is causal and independent. The mortality follow-up for the Multiple Risk Factor Intervention Trial (MRFIT) randomized cohort provides an opportunity to examine these relationships. Between 1973 and 1975, 361,662 men, ages 35 to 57, were screened for blood pressure, serum cholesterol, and cigarette smoking. Patients receiving medication for diabetes were excluded. Men in the upper 10 to 15% of coronary heart disease (CHD) risk (12,866) were randomized into the MRFIT trial. Standard casual urine dipstick determinations (Labstix) for protein were done at baseline and annually for six years. Post-trial cause-specific mortality was ascertained using the National Death Index. During the trial, 2326 (18.1%) of participants had + or higher proteinuria, and 593 (4.6%) had +2 or higher proteinuria. The presence of proteinuria during the six years of follow-up was consistently associated with higher all cause, cardiovascular disease (CVD) and CHD mortality, even after adjusting for other risk factors. The higher and more persistent the proteinuria, the greater the risk. In this data set, proteinuria is a strong and independent risk factor for CVD mortality.

Onchocerca volvulus: identification and characterization of an immunogenic eggshell protein (Oveg1).

A major antigen recognized by human sera in Onchocerca volvulus infections is a parasite eggshell protein. The cDNA clone for this antigen was isolated from a lambda gt11 O. volvulus cDNA library using antisera from patients with high microfilarial counts. Sequence analysis of the cDNA clone predicts a polyglutamine repeat near the 5' end of the cDNA, and a motif of four arginines near the 3' end, reminiscent of that found in many regulatory proteins. The cDNA was subcloned into a yeast expression vector and reagent quantities of recombinant antigen produced in Saccharomyces cerevisiae. Antisera produced to the recombinant purified protein localized the antigen to the eggshell of developing microfilariae within the adult female uterus. No other sites of Oveg1 expression were noted in adult worms, but labeling was seen in internal membrane structures of L3 larvae. Sera from infected chimps recognized Oveg1 only after infections became patent. Sera from infected humans showed reactivity to Oveg1 that varied from 39 to 95%, depending upon the geographic location.

Identification of genes required for alpha 2 repression in Saccharomyces cerevisiae.

Transcriptional repression of the a-specific genes in Saccharomyces cerevisiae alpha cells involves the concerted action of several proteins. The homeodomian protein alpha 2, together with MCM1, recruits two general transcriptional repressors, SSN6 and TUP1, to the promoters of a-specific genes. SSN6 and TUP1 then mediate repression of the a-specific genes. SIN4, another general negative regulator, is required for this repression, but unlike tup1 or ssn6 deletions, sin4 deletions cause only partial loss of repression. We have screened for other genes required for a-specific gene repression in alpha cells. In addition to recovering multiple alleles of previously identified genes required for this process (referred to as alpha 2 repression), we have identified four other genes, designated ARE1, ARE2, ARE3, and ARE4 (for alpha 2 repression). Recessive mutations in the ARE genes cause partial loss of a-specific gene repression and cause pleiotropic phenotypes similar to those resulting from mutations in SSN6, TUP1, or SIN4, suggesting that the ARE genes are general negative regulators. Based on our initial analysis, we propose that two distinct classes of general negative regulators cooperate to bring about full levels of alpha 2 repression. The sequence of ARE1 revealed that it encodes a CDC28-related protein kinase, identical to UME5, and thus suggests that protein phosphorylation plays a role in alpha 2 repression.

Association of the human CD3-zeta chain with the alpha beta-T cell receptor/CD3 complex. Clues from a T cell variant with a mutated T cell receptor-alpha chain.

The TCR for Ag, on the majority of human T cells, is a disulfide-linked heterodimer composed of TCR-alpha and -beta chains noncovalently associated with the monomorphic CD3 complex composed of the CD3-gamma, -delta, -epsilon, and -zeta chains. The interactions involved in the assembly of the various components of this multimeric protein complex are not fully understood. In this report, a variant of the human leukemic T cell line Jurkat that synthesized all of the known components of the TCR/CD3 complex but fails to express the TCR/CD3 complex at the cell surface is further characterized. This variant, J79, has a mutated TCR-alpha chain that does not affect the assembly of the pentameric form (TCR-alpha beta-CD3-gamma delta epsilon) of the TCR/CD3 complex but inhibits the assembly of the CD3-zeta homodimer with the rest of the complex (TCR-alpha beta-CD3-gamma delta epsilon----TCR-alpha beta-CD3-gamma delta epsilon zeta 2). Transfecting a wild-type TCR-alpha gene into J79 reconstituted expression of a complete functionally competent TCR/CD3 complex at the cell surface. The results indicate that the TCR-alpha chain plays a crucial role in the assembly of the CD3-zeta homodimer with the pentameric form of the TCR/CD3 complex.

Heterogeneity of protein kinase C isoenzyme gene expression in human T cell lines. Protein kinase C-beta is not required for several T cell functions.

An early consequence of stimulation of T cells via their Ag receptor is the activation of protein kinase C (PKC). It has recently been shown that PKC activity resides in a family of homologous proteins. Inasmuch as T cells are phenotypically and functionally heterogeneous, we examined the possibility that this heterogeneity may be reflected in differential expression of message for PKC isoenzyme genes. RNA from six leukemic T cell lines was probed for PKC-alpha, -beta, and -gamma message before and after activation. These studies revealed significant differences among these lines. None expressed mRNA for PKC-gamma. Whereas all cells possessed message for PKC-alpha, there was consistent variability in the level expressed. The greatest heterogeneity was seen with PKC-beta. Two cell lines, HUT 78 and HPB-ALL, did not hybridize with the beta probe under any conditions tested. We subsequently used these PKC-beta negative cells to study the role of this isoenzyme in mediating some of the effects seen with phorbol esters that directly bind to and activate PKC. Our results indicate that PKC-beta, which is expressed in some T cells, is not necessary for PMA-induced CD3 or CD4 internalization, IL-2 production, or acquisition of the p55 chain of the IL-2 receptor.