I told you so

I never have trusted cloud computing, it is akin to trusting in the kindness of strangers.

As the WSJ reports:

Large electrical storms on the east coast disrupted power for Amazon.com Inc. cloud-computing operations Friday night, causing outages for customers such as Netflix Inc. and photo-sharing service Instagram.

The Seattle-based online retailer operates data centers with servers that manage the Web operations of many other companies, a practice often called cloud computing. Power outages caused by catastrophic storms that blanketed the east coast affected Amazon's operations in Virginia.

On Saturday afternoon, Amazon was still reporting performance issues for what it calls its elastic cloud compute, relational database and elastic beanstalk services. The problems appeared to have begun appearing on the site at around 11:21 p.m. EDT on Friday.

For those old guys like me who had built global networks on their own nickle,  this was always a risky business. There was just a storm, guys, not an asteroid. You should have planned for that. Secon exits, Plan B, whatever! I have seen them all...

Prior planning prevents poor performance ... my father always said that to me!

Keen Insight into the Obvious

The ACA decision has the quote (from Mankiw sans comment) regarding economists:

To an economist, perhaps, there is no difference between activity and inactivity; both have measurable economic effects on commerce. But the distinction between doing something and doing nothing would not have been lost on the Framers, who were “practical statesmen,” not metaphysical philosophers.

Brilliant! And so true.....

Logic and ACA

Down the rabbit hole we go. A tax, no there will be no tax.

Now the Times has comments worth a comment:

In the two years since the AHCA passed, My family has saved over 2000.00. My son, 24 has remained on my policy (I had been paying 400 a month for his insurance as he began his career.) My mother's drug bill dropped by several hundred dollars.

Now I can feel comfortable that my children, both who have had earlier bouts with respiratory illness but seem fine now, will not have to be saddled with high premiums or exclusions for pre-existing conditions.

I can feel comfortable that people I come into contact with who haven't had insurance will now be able to afford it.

Perhaps this reader will tell me who is paying for this? They are apparently clueless on this issue. Health Care is not free, that is the point.  When some person makes a comment like this it is clear to me that they have not a single idea that there are consequences. Even in Aristotle's day we knew every action had a reaction, in fact for 2,000 years that was the basis of the theories of motion, not some force at a distance. Somehow or other this people have a Newtonian idea that there is some force field of zero costs that enables all of this.

Every comment the above makes has a consequence, a cost, and yet the writer is totally above reality in never recognizing them.

At the other extreme as I had said some 3+ years ago as this disaster was brewing, Government mandates must carries, services few use and many abuse, and we all pay. A sad day for America, few of us ever understand the costs side, too many live in the wonderland of Government gifts.

Rousseau at 300

"Man is born free, and everywhere he is in chains."

 I have always had mixed feelings about Rousseau. Today marks the 300th anniversary of his birth. I remeber spending quite a bit of time in Annecy on the lake in Savoy, visiting his old haunts.

Here was a man who thought we humans perfect until destroyed by society and a man who believed truly in the ideal of a social contract. He was a man also estranged from time to time from his peers but a man held up by many. In ways a counterpart of Voltaire and yet distant from him as well.

His works may seem strange to many Americans today but to the "intellectuals" of the mid 18th century they caused bells to ring.

Consider his words:

The most ancient of all societies, and the only one that is natural, is the family: and even so the children remain attached to the father only so long as they need him for their preservation. As soon as this need ceases, the natural bond is dissolved. The children, released from the obedience they owed to the father, and the father, released from the care he owed his children, return equally to independence. If they remain united, they continue so no longer naturally, but voluntarily; and the family itself is then maintained only by convention.

 Strange is it not for he was the one who abandoned his own children. But read deeper, does he justify this action, is it not now a natural progression?

After these 300 years, one should at least reflect briefly on what this man meant to us today. On the one hand the Progressives and their view of a social contract, on the other, the Individualists and their ideal of the independence of man.

Wnt and TERT Signaling

Signaling pathways in the cells have been a major focus on study for the past decade or so. The focus generally has been on what protein or gene influences what other protein or gene. A recent article in Science presents some interesting work on Wnt and TERT.

Wnt is an extra cellular signaling protein and it attaches to Frizlled a receptor and sets off a cascade that moves B catenin into the nucleus and generates Myc which is a transcription protein with together with catenin and other transcription proteins generates Tert from TERT.

To quote from NCBI:

Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity, encoded by this gene, and an RNA component which serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in oncogenesis.  

As the Science article states:

Maintaining the length of telomere, the ends of chromosomes, is essential for all cells that divide many times. The enzyme telomerase lengthens these ends, counterbalancing their shortening that occurs each time chromosomes are copied. Telomerase is essential for cell viability, and loss of its function from the loss of only one of two copies of the encoding gene can lead to the failure of stem cell renewal that is seen in premature aging conditions such as dyskeratosis congenita, aplastic  anemia, and pulmonary fibrosis. Conversely, telomerase activity is increased in many cancers  and may be required for cancer cells to maintain their telomere length...

 They continue is a rather interesting wording:

Because of the importance of telomerase expression, the signaling pathways that control TERT transcription have been extensively studied. Remarkably, many different transcription factors, including c-Myc, Sp1, nuclear factor of activated T cells (NFAT), activating protein 2B, nuclear  factor κB (NF-κB), Myb, activating transcription factor, nuclear factor 1 (NF1), and the estrogen receptor (ER), bind to the 330–base pair minimal TERT promoter and regulate transcription. In addition, a number of negative regulators bind the TERT promoter, including CTCF, elongation factor 2, p53, Ets, Mad1, Men1, and Wt1. Adding β-catenin and Klf4 to the many regulators that bind the TERT promoter is like adding one more guest to a crowded table at a dinner party.

They conclude:

It is reasonable to propose that Wnt regulates TERT given that Wnt signaling plays an essential role in stem cell self-renewal and that TERT is needed for the long-term growth of stem cells. TERT  regulation seems to require not one, but two master transcriptional regulators to assure that there is  neither too much, which may allow the growth of cancer cells, nor too little, which might lead to stem cell failure. The fi nding by Hoffmeyer et al. that both β-catenin and Klf4 are required to activate  TERT expression puts the horse (Wnt) before the cart (TERT) and provides a foundation for linking  telomerase levels and self-renewal.

The observation of the inter-cellular signalling with Wnt and its control over TERT and the telomere process is quite interesting. This may be an interesting way to incorporate many of the Turing models we have been discussing as well.

Monitoring Cable Data

The NY Times has an article regarding the intent by cable companies to charge for usage. The state:

Here in South Texas, Time Warner Cable customers have been given the online equivalent of a scale in the bathroom, a “usage tracker” that adds up all the household’s Facebooking and YouTubing. Customers who sign up for a light plan of 5 gigabytes of broadband — that’s the equivalent of two high-definition movie downloads — are rewarded with a $5 discount each month if they don’t go over. If they do, they pay $1 for every additional gigabyte. 

then continue:

Usage-based billing is seen by some as a fairer alternative to broadband caps, a term most closely associated with Comcast, which had been enforcing a limit of 250 gigabytes per Internet customer per month. Although only a small minority of customers ever exceeded the cap, it became a lightning rod for competitors like Netflix, which accused Comcast of unfairly favoring its own services.  

Now a bit of bona fides. I was COO of NYNEX Mobile, now Verizon, and SVP at Warner Cable, then Warner AMEX. I thus have some modicum of knowledge. Also as the CEO and founder of central and eastern Europe's first full fiber network I understand Internet backbone. Unlike many of the younger generation I went thru these wars before.

My observations:

1. Billing is a total nightmare. Really. It costs more than anything you hope to recover. Really. Been there done that! Why? Because customers complain and seek remedies for calls not made, bytes not used. You have to be a complete moron, I will tell you how I really feel later, to think you will win this one. Average work here. Yes, some people use nothing, lots frankly, you win, a few are hogs, you lose. So figure out what works and you will never get a complaint, or a law suit!

2. What is the cost? Zero now, almost. It does not cost much anymore, even if you are not a Tier 1 Internet backbone carrier, which all of these guys are any how. Are you just greedy?

3. The real and only reason is to establish a barrier to entry to competitors. Yes, the cable guys want to control content, that is where the money is. This is their way to do that. It is a pre-emptive strike. Perhaps there are still anti-trust laws, like bundling and the like.

The Times missed the point. The FCC is clueless on this as is Justice. It must become a total mess before anyone acts. Just watch.

But wait, the bandwidth on wireless is exploding....

What Is in a Name

I have difficulty in decoding the usage of names. Let me give several examples:

1. When back in a hospital I get called Dr. McGarty no matter what, even though I am not licensed to practice Medicine. A couple of years ago when back at the Brigham this was pandemic. For a while I thought I was in a 1950s movie of Dr Kildare.

2. In a medical specialists office I am called Dr. McGarty by the staff and depending on how well I know the specialist it is Terry or Dr McGarty.

3. In upscale professional settings such as a good law firm it is Mr. McGarty.

4. By anyone under 40 it is Terrence if they have no clue who I am. Now I never use Terrence other than in a legal context, for after all it is my first name.

5. In my local doc's office, nice local guy, his staff calls me Terrence. As if I and all the other patients were pets, Spotty, Rover, etc. I remember my first copy of Harrison's I think the 5th edition, used, the first chapter was on how to greet patients. "Mr Jones" or "Mrs Smith", well before Gloria Steinham. One demonstrated respect, and perhaps a professional approach.

6. At a trial if one wants to denigrate a witness one calls them by their first name. Old trick.

7. But what has happened to the younger set? Answer, teachers. They were the one's who established the code of human interaction, and well they went down the drain. In an academic setting it was and may still be at better institutions Prof. McGarty etc. Yet at low level institutions, such as my local Community College, it was Terrence.

So what is in a name? It tells you the "class" of the user. Yes, class, it is like the use of "huh" or "uh" or "Um". Animal grunts, resulting from the collapse of our primary and secondary educations system. Do we have problems, yes indeed, and it begins with manners.

Turing at 100

The NY Times has a piece commemorating Turing's 100th birthday anniversary today. Despite Turing's work on computers and codes, in the long run it may be one of his last papers published in August 1952, entitled (he died June 7, 1954):

The Chemical Basis of Morphogenesis, Phil Trans Royal Society London pp 37‐72, 1952

He states in the Abstract:

It is suggested that a system of chemical substances, called morphogens, reacting together and diffusing through a tissue, is adequate to account for the main phenomena of morphogenesis. Such a system, although it may originally be quite homogeneous, may later develop a pattern or structure due to an instability of the homogeneous equilibrium, which is triggered off by random disturbances. Such reaction-diffusion systems are considered in some detail in the case of an isolated ring of cells, a mathematically convenient, though biologically unusual system.

The investigation is chiefly concerned with the onset of instability. It is found that there are six essentially different forms which this may take. In the most interesting form stationary waves appear on the ring. It is suggested that this might account, for instance, for the tentacle patterns on Hydra and  or whorled leaves. A system of reactions and diffusion on a sphere is also considered.  Such a system appears to account for gastrulation. Another reaction system in two dimensions gives rise to patterns reminiscent of dappling. It is also suggested that stationary waves in two dimensions could account for the phenomena of phyllotaxis. 

The purpose of this paper is to discuss a possible mechanism by which the genes of a zygote may determine the anatomical structure of the resulting organism. The theory does not make any new hypotheses; it merely suggests that certain well-known physical laws are sufficient to account for many of the facts. The full understanding of the paper requires a good knowledge of mathematics, some biology, and some elementary chemistry. Since readers cannot be expected to be experts in all of these subjects, a number of elementary facts are explained, which can be found in text-books, but whose omission would make the paper difficult reading.

Frankly the paper has lasting insight which may surface again as we examine metastatic processes and intra/extra cellular signalling.

It should be noted that the pattern in the above Hemerocallis can be explained by Turing's work. For those who understand the wave equation with a nonlinear constraint then we see two waves of red, one in the center and one at the edge (see my paper on Turing coloring). It can likewise be argued that the flow of inter-cellular ligands in metastatic cancers follow a similar model (see my White Paper).

One can only imagine what would have happened if he had gotten further with the Watson and Crick paper, dated April 25, 1953.

LKB1 and Melanoma

LKB1 has been demonstrated to be the underlying control element in Peutz-Jeghers syndrome, a proliferative melanocytic genetically dominant disorder. It controls certain pathways and as a result can be considered as a candidate in the development and progression of melanoma. Generally LKB1 is a gene whose protein stabilizes the growth and location of melanocytes. Understanding its impact in Peutz-Jeghers allows one to examine what happens when its function is suppressed in melanoma. Albeit not an initiator in the process, its aberration in a melanocyte argues for movement and loss of control.

 

In a recent paper by Liu et al the authors examine this premise and conclude that loss of LKB1 is significant especially in metastatic evolution. As Liu et al state:

Germline mutations in LKB1 (STK11) are associated with the Peutz-Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous melanoma. By somatically inactivating Lkb1 with K-Ras activation (±p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC family kinase (SFK) YES, increased expression of WNT target genes, and expansion of a CD24⁺ cell population, which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24⁻ cells. These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing an SFK-dependent expansion of a prometastatic, CD24⁺ tumor subpopulation.

Earlier work by Zheng et al noted:

The LKB1-AMPK signaling pathway serves as a critical cellular sensor coupling energy homeostasis to cell growth, proliferation, and survival. However, how tumor cells suppress this signaling pathway to gain growth advantage under conditions of energy stress is largely unknown.

Here, we show that AMPK activation is suppressed in melanoma cells with the B-RAF V600E mutation and that downregulation of B-RAF signaling activates AMPK. We find that in these cells LKB1 is phosphorylated by ERK and Rsk, two kinases downstream of B-RAF, and that this phosphorylation compromises the ability of LKB1 to bind and activate AMPK. Furthermore, expression of a phosphorylation-deficient mutant of LKB1 allows activation of AMPK and inhibits melanoma cell proliferation and anchorage-independent cell growth.

Our findings provide a molecular linkage between the LKB1-AMPK and the RAF-MEK-ERK pathways and suggest that suppression of LKB1 function by B-RAF V600E plays an important role in B-RAF V600E-driven tumorigenesis.

Thus Zheng et al putatively identified these two pathways as sources for melanoma development. Liu et al appear to have extended this to metastasis.

Now in a paper by Bauer and Stratakis the authors provide an excellent overview of the controlling pathways. We provide a revised version of their pathway controls in a normal melanocyte below.

The LKB1 gene, also called STK11, which encodes a member of the serine/threonine kinase, regulates cell polarity and functions as a tumour suppressor. This is clearly demonstrated in the above.

Now Liu et al state regarding this pathway model:

Two independent pathways appear to be critically important in regulating cell growth in response to nutrient supply and mitogenic stimulation:

(i) the PKA/PRKAR1A-LKB1 tumour suppressor protein pathway, acting via AMPK, and

(ii) the PI3K/AKT pathway.

Recent evidence suggests that the tumour suppressor gene complex, TSC1/TSC2, orchestrates the signal from both pathways to the downstream target, mTOR, which in turn regulates the ribosomal protein S6 and 4EBP-1, a repressor of the translational initiation factor eIF4E. In this model, at times of nutrient stress LKB1/AMPK activation of the TSC1/TSC2 complex results in inhibition of mTOR and a decrease in protein synthesis. Under stimulation of mitogenic pathways, PI3K phosphorylates PIP2 to PIP3 resulting in recruitment of AKT to the membrane where it is activated by PDK1. Activated AKT inhibits the TSC1/TSC2 tumour suppressor complex leading to increased mTOR activity. In the later pathway, PTEN antagonises PIP3 action through dephosphorylation, and thus provides an ‘‘off’’ switch for regulating mitogenic pathway induced cellular growth and proliferation.

Cross talk of several other pathways appears to play important regulatory roles in the lentiginoses syndromes to include the Ras/MAPK pathway in the regulation of translation, the LKB1 pathway in cellular polarity, the AKT pathway (as well as the TSC1/TSC2 complex) in the regulation of the Wnt/GSK3b/b-Cat pathway, and the BMP pathway in the regulation of PTEN (see text for further discussion). Lastly, both PTEN and mTOR appear to have negative regulatory effects on VEGF through loss of stabilisation of the hypoxia inducible transcription factor 1 (HIF1).

When LKB1 is inactivated we have the following changes observed:

These models or Bauer and Stratakis are compelling and establish a paradigm which the work of Liu et al can be considered.

Let us go back to LKB1 and its function. From NLM database we have[1]:

LKB1 is a primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK), a necessary element in cell metabolism that is required for maintaining energy homeostasis. It is now clear that LKB1 exerts its growth suppressing effects by activating a group of other ~14 kinases, comprising AMPK and AMPK-related kinases.

Activation of AMPK by LKB1 suppresses growth and proliferation when energy and nutrient levels are scarce. Activation of AMPK-related kinases by LKB1 plays vital roles maintaining cell polarity thereby inhibiting inappropriate expansion of tumour cells. A picture from current research is emerging that loss of LKB1 leads to disorganization of cell polarity and facilitates tumour growth under energetically unfavorable conditions. Also it is known as PJS; LKB1; hLKB1.

This gene, which encodes a member of the serine/threonine kinase family, regulates cell polarity and functions as a tumor suppressor. Mutations in this gene have been associated with Peutz-Jeghers syndrome, an autosomal dominant disorder characterized by the growth of polyps in the gastrointestinal tract, pigmented macules on the skin and mouth, and other neoplasms. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized.

From the results of Shaw et al we have[2]:

AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status found in all eukaryotic cells. AMPK is activated by stimuli that increase the cellular AMP/ATP ratio. Essential to activation of AMPK is its phosphorylation at Thr-172 by an upstream kinase, AMPKK, whose identity in mammalian cells has remained elusive.

Here we present biochemical and genetic evidence indicating that the LKB1 serine/threonine kinase, the gene inactivated in the Peutz-Jeghers familial cancer syndrome, is the dominant regulator of AMPK activation in several mammalian cell types. We show that LKB1 directly phosphorylates Thr-172 of AMPKalpha in vitro and activates its kinase activity.

LKB1-deficient murine embryonic fibroblasts show nearly complete loss of Thr-172 phosphorylation and downstream AMPK signaling in response to a variety of stimuli that activate AMPK. Reintroduction of WT, but not kinase-dead, LKB1 into these cells restores AMPK activity. Furthermore, we show that LKB1 plays a biologically significant role in this pathway, because LKB1-deficient cells are hypersensitive to apoptosis induced by energy stress.

On the basis of these results, we propose a model to explain the apparent paradox that LKB1 is a tumor suppressor, yet cells lacking LKB1 are resistant to cell transformation by conventional oncogenes and are sensitive to killing in response to agents that elevate AMP. The role of LKB1/AMPK in the survival of a subset of genetically defined tumor cells may provide opportunities for cancer therapeutics.

Also Shaw et al demonstrate several ways in which LKB1 can function when activated in vivo from either a basal or non-basal state. The description can be shown in the following Figure:

Shaw et al describe the above as follows:

Model for LKB1 as a sensor of low energy and negative regulator of tumorigenesis and apoptosis. Under basal conditions, LKB1 serves as a sensor of low energy, keeping ATP-consuming processes including protein synthesis in check via AMPK phosphorylation of TSC2.

In response to stresses such as low glucose, hypoxia, nutrient deprivation, or mitochondrial poisons, LKB1 phosphorylates AMPK, which shuts off ATP-consuming processes and up-regulates ATP production to offset the elevated AMP/ATP ratio. This activity prevents the cells from going into apoptosis in response to elevated AMP. In LKB1-deficient cells, under some basal conditions, there may be increases in TOR signaling due to the lack of TSC2 phosphorylation by AMPK, resulting in increased growth or tumorigenic potential. In response to further increases in intracellular AMP, these cells have no mechanism to offset the elevated AMP and go straight into apoptosis.

However, although this is an interesting and compelling description of the metastatic driving factors, there are a multiple set of issues still outstanding:

1. Metastatic behavior implies the ability of the malignant melanocyte to migrate at will within the body. Movement of the melanocyte requires breaking of the E cadherin bonds with the adjacent keratinocytes. Thus is there a sequence of genetic changes and how does this putative mechanism relate to that of the E cadherin mechanism.

As Baas et al state:

A second prominent aspect of polarized simple epithelia is the presence of junctional complexes at the apical boundaries between neighboring cells. These junctions form an impenetrable seal between cells and provide strength to the epithelial sheet by serving as anchoring sites for cytoskeletal elements including the brush border.

We found that LS174T cells do not express junctional proteins, such as ZO-1, and are homozygous mutant for E-cadherin. By contrast, DLD-1 cells are capable of forming tight junctions and adhesion junctions when grown to confluency and appear to express most junctional compo­nents already at low-cell density.

We determined the localization of the tight junction component ZO-1 and of the adherens junction protein p120 before and after activation of LKB1 in DLD-1-W5 cells grown at very low density.

2. LKB1 is a gene related to the control from decreased nutrients. However we have the angiogenesis issue related to the increased nutrition of malignant cells. However on the counter side we have the Warburg effect as a counter to normal metabolism, namely cancer cells are anaerobic metabolic systems. What is the balance between the two?

3. Is the LKB1 mutation one of random gene mutations or is it a direct consequence of other downstream mutations? Is perhaps this loss of LKB1 a result of some induced miRNA effect in vivo?

This is an interesting result and very much worth following.

References

1.               Baas, A., et al, Complete Polarization of Single Intestinal Epithelial Cells upon Activation of LKB1 by STRAD, Cell, Vol. 116, 457–466, February 6, 2004.

2.               Boudeau J., et al, Analysis of the LKB1-STRAD-MO25 complex, Journal of Cell Science 117, 6365-6375 Published by The Company of Biologists 2004.

3.               Shaw, R.,  et al, The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress, Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3329-35. Epub 2004 Feb 25.

4.               Suh, B., B. Hille, PIP₂ is a necessary cofactor for ion channel function: How and why? Annu Rev Biophys. 2008; 37: 175–195.

5.               Tiainen, M. et al, Growth arrest by the LKB1 tumor suppressor: induction of p21 ^WAF1/CIP1 , Human Molecular Genetics, 2002, Vol. 11, No. 13 1497–1504.

6.               Trojan, J., et al, 5'-CpG island methylation of the LKB1/STK11 promoter and allelic loss at chromosome 19p13.3 in sporadic colorectal cancer, Jrl Med Gen 2000;47:272–276.

7.               Wang J., et al, Germline mutations of the LKB1 (STK11) gene in Peutz-Jeghers patients, J Med Genet 1999;36:365–368.

8.               Zheng, B., et al, Oncogenic B-RAF Negatively Regulates the Tumor Suppressor LKB1 to Promote Melanoma Cell Proliferation, Molecular Cell 33, 237–247, January 30, 2009.

9.               Zigler, M., et al, PAR-1 and thrombin: the ties that bind the microenvironment to melanoma metastasis, Cancer Res. 2011 Nov 1; 71(21):6561-6. Epub 2011 Oct 18.

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[1] http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&dopt=default&rn=1&list_uids=6794

[2] http://www.ncbi.nlm.nih.gov/pubmed/14985505

Type 2 Diabetes, Weight, Genes and Causes

In a recent paper by Perry et al, Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases, the authors have performed a genome wide study identifying genes that a prevalent in non-obese versus obese Type 2 diabetics[1] (T2). We have argued previously that the predominant number of T2 cases is driven by obesity. The authors demonstrate non obese T2 and then through a genome wide analysis, GWA, identify the putative genes.

We summarize their results and we then present several questions regarding the usefulness of the results.

The authors start by stating:

Individuals with Type 2 diabetes (T2D) can present with variable clinical characteristics. It is well known that obesity is a major risk factor for type 2 diabetes, yet patients can vary considerably—there are many lean diabetes patients and many overweight people without diabetes. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m²) compared to obese cases (BMI≥30 Kg/m²). 

Specifically, as lean T2D patients had lower risk than obese patients, they must have been more genetically susceptible. Using genetic data from multiple genome-wide association studies, we tested genetic markers across the genome in 2,112 lean type 2 diabetes cases (BMI<25 kg/m²), 4,123 obese cases (BMI≥30 kg/m²), and 54,412 healthy controls. We confirmed our results in an additional 2,881 lean cases, 8,702 obese cases, and 18,957 healthy controls. 

Using these data we found differences in genetic enrichment between lean and obese cases, supporting our original hypothesis. We also searched for genetic variants that may be risk factors only in lean or obese patients and found two novel gene regions not previously reported in European individuals. These findings may influence future study design for type 2 diabetes and provide further insight into the biology of the disease.

They then continue:

Genome-wide association (GWA) studies have identified ~50 independent loci robustly associated with type 2 diabetes. These studies have highlighted new candidate pathways involved in the disease, identified overlap with monogenic forms of the disease, and provided genetic links with correlated phenotypes.

The GWA studies of type 2 diabetes have not so far provided a greatly improved understanding of the clinical heterogeneity of the disease. Type 2 diabetes cases vary appreciably in their clinical characteristics, particularly age of diagnosis and body mass index (BMI). There is also a group of patients who may present with evidence of an autoimmune component to their diabetes, but who are not insulin dependent. In contrast, the identification of the genetic component to monogenic forms of diabetes has often explained the clinical heterogeneity observed.

Previous studies have provided some evidence of genetic heterogeneity between non-obese and obese type 2 diabetic cases. For example, the variant with the strongest effect on type 2 diabetes risk, in TCF7L2, has a stronger effect in non-obese cases (odds ratio = 1.53 [0.37–1.71] compared to obese cases (OR = 1.21 [1.09–1.35]). The effect of  FTO variation on type 2 diabetes risk depends on how cases and controls are ascertained by BMI status, but this was expected given FTO's known primary effect on BMI. In the most recent GWA studies of type 2 diabetes, risk variants tended to have stronger effects in non-obese compared to obese individuals – of 30 loci examined, 23 showed stronger associations in non-obese compared to obese individuals.

The authors conclude:

In conclusion, we report associations with the LAMA1 and HMG20A (not previously associated at genome-wide significance in Europeans) gene regions with type 2 diabetes risk. We have demonstrated that lean diabetic cases are enriched for known type 2 diabetes risk alleles compared to obese cases. This enrichment is consistent with the observation that many of the variants with the strongest effects on diabetes are associated with reduced beta cell function [1]. At the opposite end of the spectrum, obese cases presumably need fewer diabetes risk variants to push them towards diabetes, as they are already under strain from the physiological impact of obesity and insulin resistance. These data suggest a disease model where type 2 diabetes cases lie across a continuous distribution with regards to genetic/environmental risk, and betacell dysfunction versus insulin resistance aetiologies.

The conclusion is that lean or low BMI Pt with T2 has a genetic predisposition to the disorder. This is consistent with what we have been stating in our prior analyses but it fails to demonstrate what percent of the total population has such a genetic failure.

This report raises several questions:

1. Not apparent is the percent of Type 2 patients who have low BMI, <25, and the percent who have high, >30. Namely what is the incidence and prevalence of T2 in those groups? One would suspect based on generally available data that the percent of high BMI individuals having T2 is high and those with low BMI have a low percent incidence and prevalence.

2. With the genes identified in the GWA in the low BMI group, what is their function? Namely the authors should have explored the intra-cellular and intercellular pathways and their metabolic effects. Just have a gene present does not mean causality. Causality is an essential element. Presence is at best correlative.

3. There is the issue of somatic presence versus germline presence. Namely if the Pt with low BMI and gene variants, were these somatic, namely did they have this forever and if so why did they come down with T2 at some point. If not somatic, and germline then what process caused the gene mutation. What caused the gene variant? This is a key question. Also if somatic why did it take so long to present?

4. How do we define T2? I suspect the authors do so via an HbA1c measure. They seem to allude to such by taking measurements of HbA1c as well as 2 hour glucose as one would do in a classic glucose tolerance test using a 75g glucose bolus. However, I found it difficult to identify the specific definition used in the document itself.

5. Notwithstanding, there is the annoying mass balance equation, input-output=net accumulation! How do these genes change this? Do they result in lowered metabolic expenditures? But with low BMI this is not an issue. Thus are we looking at different T2 disease states?  The low BMI T2 patient has excess blood glucose due to lower uptake? lower insulin secretion? Why? What do these genes do to achieve that abnormality?

We seem left with more questions than answers. This is often the case with excess data and no paradigms to validate them.

 

Reference

Perry, J., et al, Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases, PLOS Genetics, May 2012 | Volume 8 | Issue 5 | e1002741.

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[1] http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1002741

It Is a Horse for Pete's Sake

The New Yorker has a piece which excoriates Mrs. Romney's horse. Now I am not a big horse fan, I did clean stables in New York City, got stiffed by the owner, I believe it was in 1956, St Patrick's day to be precise. The old man owner had us clean out stables in return for payment. When all done he told us we were paid by learning how to work. This was a critical life lesson, always have a contract and never trust someone you do not know. As I later dealt with many international deals I always remembered the stiffing dealt by the old man owner, a permanent limbic valence.

I also rode a bit when in New Mexico, north of Taos, great riding, and in Virginia, all western. But I do appreciate dressage and I was personally introduced to Mrs. Romney's horse this past week.

But like any sport it does take effort, expertise, dedication. Also one should remember that Bloomberg's daughter is also in the sport.

So why the uproar, from Colbert? To those uneducated I guess it looks funny. But one should remember that sixty years ago it was dominated by the US Army! Yes soldiers were the riders and the Government frequently the owner.

You see it was the cavalry which started this and when they moved to tanks then it was moved to those who could afford it. This is not an inexpensive sport. Riders, trainers, vets, stable hands, and the list goes on. But frankly the animals are magnificent.

But the New Yorker should remember, never get between a girl and her horse.

Some of the Worst Roads

Pennsylvania has some of the worst road maintenance practices in the world. Somehow they manage to take massive Interstate roads and close them to one lane on upgrades which are heavily traveled by trucks. I experienced 2-3 hour delays on I78 the other day as I observed these trucks in single file down to 20-30 mph and blockages some 6-10 miles long. The wasted fuel, time, costs, and when one passes the blockage there is no one doing anything but there is a sign proclaiming this a shovel ready stimulus job! Three years later!

Then there is New Jersey. Five lane highways, and they are expanding the NJ Turnpike an additional 3 lanes in each direction. Hundreds of people and moving machines. No delays, the trucks are doing 70+. And no Stimulus sign.

Why the difference? Is Pennsylvania that incompetent. New Jersey seems to have managed this through some of the most incompetent Governors, and we have had quite a few. Why the difference?

Medicare Costs Again

Over the past few years I have examined in detail the costs of Medicare. The conclusion was simple, yes some people benefit, while others over pay by a significant amount.

One of the many economists I have been following details his analysis, weak as it is, and he fails as do most others by not examining the details; again engineers and economists.

He states:

I get the impression that many Americans believe Medicare is financed like Social Security. They know that a portion of payroll taxes goes to Social Security and a portion goes to Medicare. So they conclude workers are paying for Medicare benefits the same way they are paying for Social Security benefits.

That isn’t remotely true, as new data from the Congressional Budget Office demonstrate.
In 2010, payroll taxes covered a little more than a third of Medicare’s costs. Beneficiary premiums (and some other earmarked receipts) covered about a seventh. General revenues (which include borrowing) covered the remainder, slightly more than half of total Medicare costs.

 Last year I published a revised version of my White Paper after a discussion in the Washington Post. Details do mater. But I want to raise another issue.

1. Suppose a couple is married and files jointly. Assume both are over 65. Assume they make jointly $350,000 of income.

2. They pay 3% of the gross for Medicare or $10,500 of their salary.

3. They pay $100 per month plus $150 in addition per month due to their salary. Thus combined they pay $500.00 per month in addition to the Medicare tax. That is $6,000 per year.

4. Combined they pay $16,500 directly for their care. Yes they had paid into Medicare for 40+ years already but we put that aside.

5. They cost the system $11,000 each or a total of $22,000 pa.

6. Net they cost $5,500 which is attributed to a Medicare Fund, which they paid into.

7. Now if they are still working they most likely are still healthy and will probably stay that way thus they really cost nothing and they are penalized $16,500 pa!

This is a strange system but after all it was invented in Washington. And it will only get worse!

Cambridge to Follow New York

The Harvard Crimson announced that the Mayor of Cambridge will try to get the city to limit soft drinks.

They state:

At Monday evening’s City Council meeting, Mayor Henrietta J. Davis proposed a resolution to investigate the possibility of limiting the size of sodas and other sugary drinks in local restaurants.

“This is motivated from a concern about health and children’s health,” said Davis, who has served as co-chair of the Cambridge Healthy Children Task Force since 1990.

“All this positive work can only go so far when the environment is filled with two size servings of soda,” Davis said.

The resolution recommends that the Cambridge Public Health Department examine whether or not a ban on large servings of soda would help to reduce obesity. In an emailed statement, the city’s Chief Public Health Officer Claude-Alix Jacob wrote that the department would have a decision ready by the fall.

Davis noted the similarities between this resolution and New York City Mayor Michael Bloomberg’s initiative to limit sodas over sixteen ounces, an act that has drawn accolades from Alec Baldwin and criticism from the New York State Restaurant Association, which labeled the act the “latest in a long list of anti-restaurant initiatives.”

 As we have explained with our previous discussion of the Bloomberg Rule, this adds costs but in reality has no effect. One suspects it is a "feel good" approach. Instead of one large soda they get six small ones.

As usual, the law of unintended consequences will follow through.

The EHR Conundrum

I have written extensively on the EHR, electronic health record conundrum, over the past few years but the best description is given in a picture by a patient in this weeks JAMA.

The author states:

No one was more surprised than the physician himself. The drawing was unmistakable. It showed the artist—a 7-year-old girl—on the examining table. Her older sister was seated nearby in a chair, as was her mother, cradling her baby sister. The doctor sat staring at the computer, his back to the patient—and everyone else. All were smiling. The picture was carefully drawn with beautiful colors and details, and you couldn't miss the message. When he saw the drawing, the physician wrote a caption for it: “The economic stimulus bill has directed $20 billion to health care information technology, largely funding electronic medical record incentives. I wonder how much this technology will really cost?”

It is really worth a view of the picture. I have seen this in various modes:


1. A good friend and superb clinician well over 40 can now be seen asking questions while typing on his screen.


2. A dermatologist friend hired an additional staff person to create her records.


3. A group of residents spend their time looking at screens rather than going to patients.


4. A gerontologist scans his patients from the nurses station, never really looking in to even see if they are alive at a nursing home.


Osler would spin over in his grave. The culture of medicine is being lost. Once we actually looked at the urine and could even identify a disorder by its smell. That is unheard of today. One even uses an electronic stethoscope to record heart beats and use AI technology to seek out beat abnormalities.


That, I fear, is the risk with the EHR.

Bloomberg and Fat

There is an article in TNR defending Bloomberg's soda ban. As the author states:

The truth is that there’s nothing inherently wrong with paternalistic government or, in the harsher, feminized shorthand of its detractors, the “nanny state.” Parents and nannies can be good or bad. No adult likes to be told how to live his life, but most of us benefit from baby authoritarianism far more than we’d like to admit. The government doesn’t want me talking on the phone while I drive? I can’t say I’ve given that vice up completely, but fear of getting ticketed makes me do it a lot less than I used to, and I may live longer as a result. The government wants me eating less salt? I don’t live in New York, but, when I heard Bloomberg was tightening the noose, I reexamined my attachment to sodium chloride and found it to be fairly weak. Bloomberg didn’t want Hitchens to smoke? Hitchens, who died this past December of throat cancer, went to his grave believing his vices remained none of Bloomberg’s business. But after being diagnosed in 2010, he conceded unsentimentally that he had long “been taunting the Reaper into taking a free scythe in my direction.” If New York City regulations persuade some of his acolytes to give up cigarettes and thereby avoid his fate, don’t let’s consider his legacy tarnished.

Now the interesting fact is that Bloomberg is an engineer by training, as are the major heads of the Chinese Government.  Now strangely this is like Chinese paternalism, controlling family size. However it is rather un-American, we Americans just don't like being told what to do. You see the vows of poverty, chastity and obedience are truly un-American. But perhaps we are developing the seven deadly sins; sloth, gluttony, envy etc.

But the real issue is as follows:

1. Excess calories cause obesity.

2. Obesity causes Type 2 Diabetes

3. Type 2 Diabetes causes kidney failure, blindness neurological disorders, heart failure, and the list goes on.

4. The sequellae to Type 2 Diabetes can be managed, albeit at a high cost and for an extended period of time.

5. Thus calories are a straight line to massive societal costs.

The question then who pays for this? That is the key point.

1. If we want total freedom then we must insist on allowing the costs to fall where they may. If you do not want to be told what to do then we, the tax payers, will not have any duty to care for you. Like that glutton in Monty Python, one more mint, and kaboom!

2. If we demand society, namely the taxpayer foot the bill for the gluttons, then we have free riders getting a benefit, or the rest of us incurring the liability. This is clearly an unjust situation. Jut Refer to Aristotle Nicomachaen Ethics.

3. However if we demand justice then those gluttons must pay if we allow freedom, namely a non-nanny state. The question then is how to get them to pay? Bloomberg denies this alternative and he wants to stop them.

4. The Bloomberg solution has costs. There will be costs to train, costs to comply, costs to report, and costs for failures, and costs to police. And yet the proposal totally fails to address the real problem, calorie intake. For the true problem, total calories, not soda, must be addressed in some other fashion.  Further he focuses on a large soda not on the very product itself. The consumer can disintermediate, get several smaller one. This is a costly and unworkable solution, it will not solve the problem. In fact it is an arrogant solution, and lacking in true recognition of the problem.

5. How to solve the problem. Two ways, both economic. Tax input or tax output and use the funds to pay for the sequallae. It work well on cigarettes, mainly because it was tobacco. But here we have carbs, and their calories. So we can tax all carbs, or tax per excess BMI. Just a simple proposal, since we already have the IRS doing health care compliance, we can have them do weight compliance as well. Thus for example, we can pass a law that requires every person to present themselves at the IRS office for a weigh in once a year. Then for every pound over their maximum we charge then an additional, say, $100 per year. If your maximum weight is say 150 pounds and you weigh 200, you must pay an additional $5000 per year. Imagine, the deficit gone in just one year or less. However one could imagine morbidly obese IRS agents, kindred TSA types, weighing in all of us taxpayers.

Obesity

Remember:

Input Less Output = Net Accumulation

that is a tautology, and a law of nature. The NY Times has a long piece on obesity. It states:

The causes of obesity are everywhere. Societal factors play a big role: the lack of safe places to play, walk or bike; sedentary jobs; less time devoted to cooking and more eating out; bigger portion sizes in packaged and prepared food; and incessant marketing of junk foods that are high in calories. Sugar-sweetened drinks accounted for at least 20 percent of the increases in weight in the United States between 1977 and 2007, according to one study cited by the institute. 

The causes of obesity dear reader are in yourself!  Fifty years ago we walked a mile to school, a mile home for lunch, a sandwich, a mile back and then a mile back home at days end. Then I would deliver newspapers on a ten mile route with 123 customers spread all over hell and gone. There was no school lunch, no breakfast, and never had deserts. No money.

Then when running my companies in central Europe, Czech Republic, Greece, Poland, Russia, portions were small and deserts were unheard of.

The worst offender if the Department of Agriculture and its food programs. It is food for the porcine. We should dismantle the program totally. Let kids walk, let them bring their lunch or walk home. Exercise and limited lunches are key. And breakfast at school, just look at the calories of a typical DoA breakfast, it exceeds 1200 cal! That is 70% of the daily maximum intake just there. Then lunch, another 1200. No wonder we have problems, as with so much else, it is the Government!

The Times continues:

The institute says that a major cut in obesity rates will require multiple strategies on a population-wide scale. This will be even more challenging than the fight against smoking. But there isn’t any choice if we want to protect the public’s health, the strength of the economy and the government budget. 

 Nonsense. The solution is to just control yourself. Tax weight, tax carbs, and disband the DoA!

The Annoyance of Facts

Kaiser has had an interview with a former Government bureaucrat who states:

If the whole law goes down, the death rate in the United States will go up beginning in 2014. Because we know that the number of uninsured people will not go down, it will go up, and that growth in the number of uninsured people increases the number of people who die, so it’s pretty straightforward as far as I can tell. We’ll also have enormous chaos in the delivery system, but how that will play out exactly is hard to know. 

 What is the basis of that statement. People will still be served, no one will be turned away. What will be the cause of this increase. In addition since the law has not yet fully gone into effect, how can there be an increase based on no law if no law was in existence. I may be the Abelard of Health Care but his logic is empty!

He then continues:

As best as anyone can tell, the reaction to the health law has been founded in an extraordinary amount of misinformation about what’s actually in it and what it will actually do. And it seems to me there’s no better way of educating the public about what the law will do and what effects it will have than just actually proceeding to implement it. I think when people begin to see exchanges offering a range of subsidized insurance products, when they begin to see some of the other things that are happening and not happening as a result of the legislation, public opinion will catch up. 

 No perhaps I am not "anyone" but I did read each version and the last final one three times in detail as this blog demonstrates. It is a nightmare! I have repeatedly detailed line by line. And he has the gall to say that:

And it seems to me there’s no better way of educating the public about what the law will do and what effects it will have than just actually proceeding to implement it.

We saw that same arrogant attitude from Congress. It is no wonder that people are so opposed. And also if obesity causes Type 2 Diabetes and if Type 2 Diabetes is the major cost element in health care cost explosions then perhaps the man would show by example and take off the weight to reduce the risk.

And I Have a Bridge for Sale

Today in the NY Times Romer is giving out advice again. But remember it is the very same Romer whose projections on unemployment we have been tracking for almost the past four years, never even close!

I agree that we need more effective fiscal and housing policies. But neither is likely to happen, at least not before the presidential election. As a result, the Fed is the only plausible source of immediate help for the American economy. It was set up as an independent body precisely so that somebody can do what’s right when politicians can’t or won’t. 

Then she suggests:

After the Fed has pushed interest rates down to zero, its main remaining tool is communications. It can affect expectations of future growth and inflation, which can have powerful effects on consumer spending and business investment today. But to have a big impact, the monetary actions need to be bold — and pursued with gusto. In an earlier column, I discussed one of economists’ favorite examples of such a policy: setting a target for the path of nominal gross domestic product. 

If the Fed doesn’t want to do something as drastic as adopting a new operating procedure, it could at least make any smaller actions it takes more effective. The previous rounds of quantitative easing may have done little to improve expectations because their size and duration were limited in advance. If the Fed does another round, it should leave the overall size and end date unspecified. Or, better yet, the ultimate scale and timing could be tied to the goals the Fed wants to achieve. 

 Frankly leadership is totally lacking, across the board. It appears that the folks in DC are totally clueless but that perhaps is not totally true. We have shown for four years that the FED has just pumped up the banks and then allowed then to continue to play with money mortgaged on our grandchildren's future. Then we also watch as Fiscal policy runs amok, again total lack of leadership.

Currently the FED is just an observer.A nice place to sit and drink coffee and watch others mess things up. But following the above somewhat vague suggestions based on her track record, please!

Columbanus and the First Individualist

Columbanus was somewhat of a unique individual amongst those at the end of Roman Empire, is such an end can be stretched to the beginning of the seventh century. He stands out for a multitude of reasons that recent authors have noted. Within the past two years three biographies of the wandering Irish monk have been written and they each have certain positive attributes. I review each accordingly. The three books are those by Tristram [[ASIN:1856076865 Columbanus: The earliest voice of Christian Ireland]], Reynolds [[ASIN:0321338898 Columbanus: Light on the Early Middle Ages (Library of World Biography Series)]] and Richards [[ASIN:1845401905 Columbanus]]. I will review each in turn but there is some commonality I shall include in each.

Reynolds has written a splendid work on Columbanus. Of all that I have read his is clearly the best. It is clear, well written, and concise, covers all the points, lacks the risky speculation of others, and fills in the gaps of the world around Columbanus.

Chapter 2 is a summary of what his youth may have been like. There is a great deal available on early Ireland in this time but unlike other areas there were no real cities or centers of humanity, the country was highly disperse and the ruling class was fluid. In addition there was often war like interactions that had been an inherent part of the Irish culture and perhaps that also contributed to the temper we see arising in Columbanus.

Chapter 4 describes his entry into the Monastery. He goes from one at Cleenish on the north end of the Shannon onto Bangor the dominant one at the time. The author makes an excellent reference to the writings of Columbanus at this time on what was to become the Three Chapters controversy. One of the key questions would be; how did the Irish perceive these issues, which were often weighted by Platonic understanding. For example did they have access to Plotinus and they clearly must have been fluent in Greek since many of these writings were in the original Greek. The author has a good discussion on pp 34-35. On p 37 there is a brief discussion on his leaving Bangor and going to Gaul. The details are brief.

In Chapter 5 the author makes a detailed discussion of the "white martyrdom" of leaving Ireland for good. However there is the potential forced return we see later and one may ask how these relate. Chapter 6 is a superb discussion of the Merovingians. The author has done a great job in a few pages of laying out the players, the culture and the issues. However there is the knowing issue of just how well they managed to communicate. This is somewhat discussed out on pp 50-51. Namely the Irish had Latin, as did the Merovingians, but the pronunciation and localisms were significant. It is never clear if Columbanus managed to develop a proficiency in the native Frank language, itself with significant regional variants. On p. 50 when Columbanus enters the land of the Franks one wonders about the communications. Irish was not spoken in the Frank territory nor does it appear that the Irish spoke the Frankish tongue. Latin was a lingua franca but pronunciation and dialects would yet have prevailed. One need look no further than Gregory of Tours and his Latin, a highly clumsy and fragmented Latin, nowhere Ciceronian. Likewise the Latin of Gregory of Rome, the Bishop of Rome, was simple but an amalgam of Roman political style of the late sixth century.

Chapter 7 discusses the battle with the bishops. The author does a superb job in this area. The Irish were egalitarian. They were the first individualists. As such they did not see any reason to be managed by bishops. This would be an ongoing battle for Columbanus. Chapter 8 is a discussion of the miracles. Frankly the discussion of Columbanus and the bears is always delightful but these in many ways is classic for what at the time were people considered saints.

Chapter 9 is quite interesting for it brings Columbanus to the Lombards in and around Milan and to Bobbio his final monastery. Here there are many issues brought up by the author. The Lombards were Arian, namely Christ was from God the Father, not another personhood. Second Columbanus as noted on p 88 he notes "the Irish valued a man's principles more than his position" was in essence the central tenet of individualism. He was not a subject but a person. Further the author states, "Columbanus suggested disobedience if the pope were in error" is noted by the authors as a basis of what one was to see in the Reformation. One could suggest likewise it was also the individualistic nature of the Irish, again one of the only countries NOT occupied by Rome.

There are a few weaknesses, in my opinion.

First, the bibliography is written in a manner which is nearly impossible to read. All references are combined in a single paragraph. Whether this is the author, the publisher, or the editor it is truly a poor and ineffective choice.

Second and this is a question of intent, the book is almost an academic treatise, yet there are no references to sources.

Third and this is a significant issue there are no direct quotes from Columbanus. Many of his works are readily available and hearing his voice would have been useful. Perhaps a new translation would have merit here however.

Fourth, it would have been quite helpful to have contained some of the dialog between Gregory and Columbanus. I understand the problem, namely the Latin is the original, and translations are often poor, but a key point of insight would have been a better understanding of that dialog. Jonas may refer to it but it may very well be a powerful analysis on its own as a window to the new world of the individual versus the subject, the new world view versus the old world view.

As a general note amongst all of the books reviewed, the spelling of names is nowhere consistent. The problem is the multiplicity of sources. This of course is compounded when the spelling is from multiple languages as well.

Why is it useful to understand Columbanus? That in a sense is the underlying theme of each of the three books mentioned. It is especially critical to understand the period between 600-650 AD. As stated by Reynolds in his title, it was the Early Middle Ages, NOT the Dark Ages.

The reasons for better understanding Columbanus and this particular period in history are as follows:

1. Columbanus came from Ireland, and Ireland was never part of the Roman Empire. Thus his world view and that of all the free Irish at the time was not colored by Roman world views. They were never to that point a captive people, they were free and individuals. Thus they belonged to themselves and not to an Empire. Religion was personal.

2. Gregory came from Roman ruling class, a grandson of a Pope. Gregory was effectively at war with Constantinople and the Eastern Church. Gregory did not allegedly understand Greek, Columbanus did, and Gregory was in a sense the last Roman. The Empire was entrenched in Constantinople, and it looked eastward, worrying about Persia. Gregory looked westward, and saw opportunities in the Church in the tribes now living there.

3. Gregory is at odds with Columbanus and the Irish. Gregory was from a world of Groups, one belonged to Rome, one belonged to the Church, and one belonged to the Empire. One was never an individual. The clash was I believe at the heart of the battle between the two. The evidence of that is that Gregory sends an Italian, Augustine, to Canterbury to rule the Church, where logically the Church had a whole nation of educated scholars and devoted believers next door in Ireland. That act was the poke in the eye by Gregory against Columbanus and all Irish and was, in my opinion, the beginning of the battle between England and Ireland which continues to this day.

4. The Arian faith was that of a single God, devoid of the complexities placed and piled atop one another by the early Church Greek Fathers, including the Trinity. The Arians in many ways paralleled the same path seeing humanity in Jesus but not the complexity of Trinitarian Christology. In a sense there is a strong parallel between the Arian faith in a single God and the position of Christ as with the other single God beliefs that included Jesus. The relationship therefore between Columbanus and the Lombards, his work with Theodelinda, the Lombard Queen, and the ability to build his final open monastery in Bobbio was a tribute to his ability to cross the line while maintaining his faith.

5. Columbanus thus represents the advent of the individual, in the context of both the State and the Church. Although respectful of the Bishop of Rome, he showed no humbling before him when it came to discussions of faith. He also showed no bowing before Kings and Queens, he understood how to deal with them. In many ways he was an example of a modern man. There were no national boundaries for Columbanus.

6. In conclusion, I argue that there were no Dark Ages, just a transition from a salve based Empire transitioned into a Middle Ages, which in many ways was a long progression into modern society. The Dark Ages is a term used oftentimes in ignorance. Gibbon talks of the Fall of Rome, was there also a Fall of Carthage? We do not see the Fall of Egypt, Greece, and Persia. Why just Rome? I would argue it was in tune with the British Empire and its world view. Here with Columbanus we have the Birth of the Individual, a single person who can cross lands, tribes, cultures, languages, religions, and talk to a Pope as an equal in thought.

You Cannot Make This Up

The Hill reports on the plan proposed by two left wing Congress people. It is akin to taking on more ballast when you have split your bottom open. Who in their right mind would ever think of this.

The Hill states:

Sen. Bernie Sanders (I-Vt.) and Rep. Elijah Cummings (D-Md.) on Thursday proposed a new tax on Wall Street trading that would raise more than $250 billion over 10 years in order to pay for a new plan to have the federal government offer dental health insurance coverage to millions of Americans.

The two members proposed legislation that would impose a "financial transactions" tax on equity trades that would collect $2.50 for every $10,000 traded, which would cover stock and bond trades. That language would reportedly raise an estimated $288 billion over 10 years, enough to cover the expected $25 billion per year cost of the new dental plan.

 What frankly is basic dental care. Back in the 1950s false teeth were common. Pull out the old ones and glue in the new. Cheap, it worked. Since then we have fluoride, and caries have gone near to zero. Dentists are depending on old folks.

Are we expected to pay for implants? That can be $8,000 per tooth! Are these characters real. Why not keep spending until we are not just broke ... but well Greece, really. I remember when I took a friend from out of the US across the New Hampshire - Vermont border and told him to have passport and visa at the ready. Perhaps that was not a real joke.

This is why people look at Congress and ask if they have a clue!

Comments by FED Chairman

The FED Chairman spoke today regarding the economy. First the drags on the economy we all know:

However, some of the factors that have restrained the recovery persist. Notably, households and businesses still appear quite cautious about the economy. For example, according to surveys, households continue to rate their income prospects as relatively poor and do not expect economic conditions to improve significantly. Similarly, concerns about developments in Europe, U.S. fiscal policy, and the strength and sustainability of the recovery have left some firms hesitant to expand capacity. 

The depressed housing market has also been an important drag on the recovery. Despite historically low mortgage rates and high levels of affordability, many prospective homebuyers cannot obtain mortgages, as lending standards have tightened and the creditworthiness of many potential borrowers has been impaired. At the same time, a large stock of vacant houses continues to limit incentives for the construction of new homes, and a substantial backlog of foreclosures will likely add further to the supply of vacant homes. However, a few encouraging signs in housing have appeared recently, including some pickup in sales and construction, improvements in homebuilder sentiment, and the apparent stabilization of home prices in some areas. 

 And he continued:

Even as fiscal policymakers address the urgent issue of fiscal sustainability, a second objective should be to avoid unnecessarily impeding the current economic recovery. Indeed, a severe tightening of fiscal policy at the beginning of next year that is built into current law--the so-called fiscal cliff--would, if allowed to occur, pose a significant threat to the recovery. 

Moreover, uncertainty about the resolution of these fiscal issues could itself undermine business and household confidence. 

Fortunately, avoiding the fiscal cliff and achieving long-term fiscal sustainability are fully compatible and mutually reinforcing objectives. Preventing a sudden and severe contraction in fiscal policy will support the transition back to full employment, which should aid long-term fiscal sustainability. At the same time, a credible fiscal plan to put the federal budget on a longer-run sustainable path could help keep longer-term interest rates low and improve household and business confidence, thereby supporting improved economic performance today. 

A third objective for fiscal policy is to promote a stronger economy in the medium and long term through the careful design of tax policies and spending programs. 

To the fullest extent possible, federal tax and spending policies should increase incentives to work and save, encourage investments in workforce skills, stimulate private capital formation, promote research and development, and provide necessary public infrastructure. 

Although we cannot expect our economy to grow its way out of federal budget imbalances without significant adjustment in fiscal policies, a more productive economy will ease the tradeoffs faced by fiscal policymakers. 

 These are well known generalizations. Simply stated we are still in the tank and Congress and the current President must do something but not too much. The incentive comment is a truism. The alternative? Dis-incent this sector? There were no specifics here, no sharp end of the world warnings, and no look to what happens a la Europe.

There must be an adult somewhere who can lay down the warning that will activate the public response.