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Fig. 1.

Isolated ventricular myocytes from goldfish heart after exposure to 60 min hypoxia in a solution containing Trypan Blue. Most cells retained the elongated shape of those maintained under normoxic conditions, but some were unable to exclude the dye (left), indicating cellular damage. Scale bar, 50μ m.

Data analysis

Data obtained from the intracellular and cellular hypoxia experiments were transferred to Microsoft Excel spreadsheets; -tests and analysis of variance for repeated measures (ANOVA with Fisher PLSD and Scheffe -test; Statview) were used to determine statistical significance (<0.05) among group means; results were expressed as means ± s . e . m .

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Transmembrane intracellular recording techniques were used to monitor the effects of moderate hypoxia (6.1±0.2 kPa) on the configuration of ventricular action potentials in goldfish heart. Cardiac action potential duration (APD) was decreased in all experiments ( N =5). As previously observed ( Cameron et al., 2003 ), there was a significant ( P <0.01) reduction in APD at 90% of full repolarization (APD 90 ) after 10 min of exposure to substrate-free hypoxia ( Fig. 2 ). Mean APD 90 under normoxic conditions was 575±24 ms; after exposure to hypoxia, this value fell to 488±12 ms, a decrease of 15.1%. APD at 50% of full repolarization (APD 50 ) was not significantly reduced. There were no significant effects of hypoxia on any other electrophysiological parameters, including resting membrane potential, action potential amplitude or slope of action potential upstroke.

Fig. 2.

Effects of moderate, substrate-free hypoxia on ventricular action potential duration (APD) in the isolated goldfish heart. APD in hypoxia was significantly shortened at 90% of full repolarization, but not at 50% (=5). Inset shows representative action potential configuration in one experiment (normoxia at left). Values are means ± 1 s . e . m . **Significantly different from values recorded under normoxic conditions (<0.01).

To examine the possibility that APD shortening in hypoxia was caused by the activation of K ATP channels, the effects of the channel antagonist glibenclamide (5 μmol l –1 ) on hypoxia-induced shortening were monitored in isolated hearts. Simultaneous exposure to both glibenclamide and hypoxia abolished the reduction in APD characteristic of hypoxia alone ( N =3; Salvatore Ferragamo Casual lace akA7LPUUwk

Fig. 3.

Effects of glibenclamide (5 μmol l), a K channel blocker, and l -NAME (50 μmol l), an inhibitor of nitric oxide synthase (NOS), on the percentage change in action potential duration at 90% repolarization (APD) induced by hypoxia in goldfish ventricle (=4). Hypoxia-induced APD shortening was eliminated by simultaneous exposure to either glibenclamide or l -NAME. Values are mean change± 1 s . e . m .

To determine whether NO plays a role in cellular responses to hypoxia in goldfish, the effects of the NOS inhibitor l -NAME were studied in isolated hearts and in ventricular myocytes. Hypoxia-induced shortening of APD 90 was eliminated by previous exposure to 50 μmol l –1 l -NAME ( N =4; Fig. 3 ).

There are a few factors contributing to this overwhelm, and progress — or a lack thereof — is at the crux:

We’re addicted to meaningless progress. We fail to define our meaningful goals. We lack a method for tracking our progress.

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And there’s one more factor to be conscious of: uncertainty. When you’re doing new things, mapping new territory, you rarely know how long the journey is going to take, because no one’s made the journey before. A concept that we can distill down to the phrase: Everything takes longer than you think it will.

The writer Oliver Burkeman recently introduced me to Hofstadter’s Law, which ingeniously captures this dilemma:

Hofstadter’s Law: It always takes longer than you expect, even when you take into account Hofstadter’s Law.

Hofstadter’s Law:

Wikipedia elaborates: “The recursive nature of the law is a reflection of the widely experienced difficulty of estimating complex tasks despite all best efforts, including knowing that the task is complex.”

Because everything takes longer than you think it will — even when you know it will take longer than you think it will — tracking progress is crucial. If you’re not going to hit the finish line on time, the only way to stay engaged is to feel, at the very least, a satisfying sense of momentum.

So whenever I’m feeling overwhelmed, I ask myself:

I’m currently developing a new podcast called GivenchyShark Lock KneeHigh Leather Wedge Boots ZcawzPWlZN
, launching this October 2017, which requires me to conduct 30 interviews, create 10 episodes, and land 2 sponsors. And each of the interviews has multiple mini-phases: booking the interview, conducting the interview, and editing the interview. It’s a lot to do, and I was feeling a little overwhelmed.

So I bought a 4-foot-wide roll of kraft paper, and I created a roadmap of everything I have to do over the next two months to reach launch. And I built in “progress trackers” for all the key pieces. This is the roadmap:

Here’s all the things it tracks:

It also tracks some other stuff, but you don’t need that much detail. The point is, there are lots of things that I get to cross off as I track my progress: weekly tasks, interviews booked, episodes completed, sponsors landed, etc.

It’s worth noting that I am also tracking all of these items in a Google spreadsheet, but having a digital document gives me zero feeling of progress. You need the analog for that: You need to be tracking your progress by writing things down . We need to see our progress, writ large in the physical world, to feel it.

The minute I created this roadmap, I felt more grounded, motivated, and in control. I can see the path forward, and I can see myself progressing down that path. It’s hard to overestimate how good this feels.

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